Tunneling CARs: Increasing CAR T-Cell Tumor Infiltration through the Overexpression of MMP-7 and Osteopontin-b

Authors

Stacey Van Pelt, Graduate Program in Immunology and Microbiology, Baylor College of Medicine, Houston, Texas.
Mark White, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas.
Candise Tat, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas.
Devyn Hooper, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas.
Lindsay J. Talbot, Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.
Mary Kathryn McKenna, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas.
Rohan Fernandes, The Institute for Biomedical Sciences, School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia.
Cliona M. Rooney, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas.
Bilal Omer, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, Texas.

Document Type

Journal Article

Publication Date

11-3-2025

Journal

Cancer immunology research

Volume

13

Issue

11

DOI

10.1158/2326-6066.CIR-25-0149

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy against hematologic malignancies but has struggled to achieve comparable success in solid tumors. A key obstacle in solid tumors is the extracellular matrix (ECM), which impedes CAR T-cell infiltration. In clinical trials, neuroblastoma has shown responsiveness to GD2-directed CAR T-cell therapy; however, the failure of GD2.CAR T cells to effectively clear bulky disease-characterized by dense ECM-highlights the critical challenge of infiltration. In this study, we demonstrate that GD2.CAR T cells exhibit a unique infiltration restriction compared with other CAR T cells and endogenous T cells. A separate analysis of clinical datasets identified MMP7 and SPP1 [which encodes osteopontin (OPN)] as candidate genes to improve the infiltration of GD2.CAR T cells as these were upregulated in tumor-infiltrating leukocytes. MMP-7 and OPN overexpression enhanced CAR T-cell extravasation and interstitial movement in ECM-dense environments in vitro. Overexpression of either OPN or MMP-7 significantly improved tumor infiltration in a xenograft model of neuroblastoma. This resulted in improved tumor control and a survival extension in OPN-GD2.CAR T cell-treated mice compared with unmodified GD2.CAR T cells. OPN overexpression did not increase off-target infiltration into healthy tissues or promote tumor metastasis, highlighting its potential for safe therapeutic application. Our study provides a framework for further exploration of gene modifications to improve CAR T-cell infiltration in solid tumors and identifies OPN as a candidate to explore in this regard. See related Spotlight by Gasparetto and Chiarle, p. 1698.

APA Citation

Van Pelt, Stacey; White, Mark; Tat, Candise; Hooper, Devyn; Talbot, Lindsay J.; McKenna, Mary Kathryn; Fernandes, Rohan; Rooney, Cliona M.; and Omer, Bilal, "Tunneling CARs: Increasing CAR T-Cell Tumor Infiltration through the Overexpression of MMP-7 and Osteopontin-b" (2025). GW Authored Works. Paper 8157.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8157

Department

Medicine